We
use Structural Molecular Biology (mainly X-ray crystallography, but including NMR
and EM) to study Developmental, Cellular, and Cancer Biology. Projects are
based around investigating the structural biology of protein-RNA and
protein-protein interactions. Details of specific projects are listed below:

Gene Expression in Single Stranded Negative
Sense RNA Viruses:

Bunyavirus nucleocapsid proteins both protect the RNA from
degradation in the cell, and interact with proteins such as the RNA dependent
RNA polymerase to regulate gene expression and replication. We (collaboration
with Dr.
John Barr) have solved the crystal structure of N proteins from Crimean
Congo Hemorrhagic Fever Virus, Bunyamwera Virus and Schmallenberg Virus, with and without RNA bound. We have
used these structures to interpret virus biology, and there is the possibility
of anti-viral therapies via structure based drug design.

We are also
investigating RNA binding proteins from the
human Respiratory Syncytial Virus.

We are
investigating the structural biology of a variety of RNA binding proteins that
control translation, splicing, RNA localisation and
stability.

Pumilio is a sequence
specific RNA binding protein, and a founder member of the Puf
family of RNA binding domains. We have solved the structure of the Pumilio Puf domain (see Figure, top right) and determined that it
has a novel RNA binding fold. In the developing Drosophila embryo, Pumilio binds to the 3prime UTR of hunchback mRNA and recruits Nanos into a
complex which represses translation. This defines the posterior of the
embryonic anterior-posterior axis. In order to repress translation, the Pumilio:RNA:Nanos complex recruits
another cofactor: Brat (Brain
Tumor). We have also solved the structure of the Brat NHL domain, and proposed
the interaction surface between Pumilio and Brat. We are continuing to
investigate the structure and function of this repression complex using structural and biochemical techniques. Dazlis a member of the RRM containing DAZ
family of RNA binding proteins. Dazl appears to
interact with the Pumilio homologue Pum2 in order to control translation of
specific mRNAs during differentiation of germ cells; the Dazl:Pum2
complex therefore appears to play a critical role in spermatogenesis. We aim to
solve the structure of Dazl in complex with RNA and
protein cofactors.

Vts1 is a homolog of Smaug, which
represses nanos
translation. We have solved the solution structure of Vts1 in complex with RNA
by 3D NMR.

SAM68 is a KH domain containing RNA binding protein that regulates
alternative splicing of CD44 pre-mRNA changing the binding characteristics of the
CD44 cell adhesion molecule. We are using a structural biology approach to
investigate the mechanism of regulated splicing.